Haloperidol is a power anti-psychotic drug, but has both short- and long- term toxicity. While the short-term toxicity may be related to the non- selective nature of haloperidol binding to dopamine receptors, some of the long-term irreversible toxic effects have been suggested to be due to metabolic goal of this research proposal is to design and synthesize haloperidol analogs which could not be metabolized to compounds known to be toxic. In addition, advantage would be taken of the high binding affinity of haloperidol to all dopamine receptor subtypes, to modify the structure of haloperidol for selectivity towards the D-4 receptor subtype.. This current research proposal therefore is designed to achieve the following specific objectives: 1) to design analogs of haloperidol which cannot be metabolized to MPP+-like species; 2) to synthesize and characterize the proposed agents, for evaluation at the dopamine receptors; 3) to conduct a 3-D QSAR studies on published D-4 ligands and suggest a pharmacophore model for D-4 ligand binding; 4) to design new analogs by incorporating D-4 pharmacophore model for D-4 ligand binding; 4) to design new analogs by incorporating newly designed analogs and characterize them; and 6) to evaluate the binding profile of the synthesized compounds at the D-2, D-3 and D-4 receptors. Twenty-seven analogs will be the primary focus of this research proposal. However, additional compounds will be proposed and synthesized based on initial SAR data generated in the proposal.